PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) has a complex mode of inheritance, and the combined effect of the now well replicated late-onset AD genetic risk loci are estimated to account for less than 40% of its genetic risk. There is no cure yet for this devastating neurodegenerative disease that affects approximately 5 million Americans, and the current treatments are only capable of ameliorating the symptoms. Therefore, it is imperative to gain a better understanding of each of the genetics factors that are linked to the development of the disease, especially in underrepresented minorities such as African-Americans, with the goal of unifying this information into better informed designs for therapies and possibly preventive interventions. Importantly, most genetic studies of AD have been conducted utilizing subjects primarily of European descent, yet AD is twice as prevalent in African-Americans. Meanwhile, studies addressing AD in African-Americans have revealed different AD risk variants from those identified in subjects of European descent. Given these disparities, the goals of the proposed study are to (1) identify specific biological pathways, and their genes and genetic variants that may impact the development of AD differentially in African-Americans versus subjects of European descent, by implementing a gene-set enrichment paradigm using pre-existing genome-wide association study (GWAS) datasets specific to these two populations, and (2) to determine if additional pathways, and their genes and genetic variants can be discovered by using results from existing whole exome sequence datasets. This project has the goal of integrating information that could lead to better informed designs for therapies and possibly preventive interventions, which could potentially be tailored to AD in African- Americans.